US6936733B2 - Method for preparing disodium 2,2'-dithiobis(ethanesulphonate) - Google Patents

Method for preparing disodium 2,2'-dithiobis(ethanesulphonate) Download PDF

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US6936733B2
US6936733B2 US10/333,422 US33342203A US6936733B2 US 6936733 B2 US6936733 B2 US 6936733B2 US 33342203 A US33342203 A US 33342203A US 6936733 B2 US6936733 B2 US 6936733B2
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Jean-Bernard Cazaux
Eric Manginot
Marc Veyrat
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Lantern Pharma Inc
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BioNumerik Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
    • C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds

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  • the present invention describes a novel process of industrial preparation of disodium 2,2′-dithiobis(alkylsulfonates), and in particular the preparation of disodium 2,2′-dithiobis(ethanesulfonate) (dimesna).
  • Dimesna (as well as its monomer, mesna) is a therapeutic agent useful in particular as a chemoprotectant for certain types of cancers by reducing the toxic effect of Platinum complexes commonly used in chemotherapy (like cisplatin).
  • a therapeutic agent useful in particular as a chemoprotectant for certain types of cancers by reducing the toxic effect of Platinum complexes commonly used in chemotherapy (like cisplatin).
  • Patent PCT Application WO 98/14426 is a therapeutic agent useful in particular as a chemoprotectant for certain types of cancers by reducing the toxic effect of Platinum complexes commonly used in chemotherapy (like cisplatin).
  • intermediate (III) is not isolated. It is directly transformed by heating in the presence of oxygen to disulfide (Ia).
  • a common problem in the synthesis of mesna or dimesna resides in the presence of many impurities in the desired product. These impurities are usually salts like sodium bromide or acetates generated by the current synthetic processes. The necessary removal of such impurities represents an important waste of time and money.
  • the present invention describes a novel process which allows the synthesis of disodium 2,2′-dithiobis(alkylsulfonates), and in particular the synthesis of mesna, without the common impurities resulting from the previous processes.
  • Hal represents a halogen atom, in particular a bromine atom
  • M represents sodium or potassium atom while n represents an integer from 0 to 2.
  • Steps (a) and (c) are preferentially carried out by heating.
  • M represents preferentially sodium.
  • This invention is therefore about the industrial preparation process of a disulfide of general formula (I) in which n represents an integer from 0 to 2, with the following steps:
  • sodium thiolacetate CH3COSNa from step (a) can be obtained by reacting thiolacetic acid with a base containing the metallic counterion M, for instance NaOH or KOH when M represents sodium or potassium.
  • M represents sodium
  • step (a) is carried out by heating at a temperature superior to ambient temperature, for instance at a temperature between 25 and 100 degree Celsius, particularly between 75 and 85 degree Celsius.
  • the base necessary to hydrolyze the thiolacetate intermediate in step (b) is preferentially NaOH or KOH. Due to the exothermic character of the reaction, the reaction mixture resulting from step (a) is preferentially cooled to a temperature closer or inferior to ambient temperature (for instance if the preferred temperature for step (a) is between 75 and 85° C., step (b) is preferentially carried out with an initial temperature between 45 and 55° C., or even at a temperature between 0 and 45° C.).
  • the pH of the reaction mixture should be between 6 and 8, preferentially between 6.5 and 7.5 and more preferentially between 7 and 7.2.
  • the acid used in this neutralization is preferentially acetic acid, although any other suitable acid can be employed.
  • step (c) the reaction mixture is preferentially heated at a temperature superior to ambient temperature, for instance at a temperature between 30 and 90° C., preferentially between 50 and 60° C.
  • Oxygen is bubbled in the reaction mixture at a pressure between 0 and 5 bars, preferentially at atmospheric pressure.
  • hydrogen peroxide in approximate stoichiometric amounts can be used in place of gaseous oxygen.
  • Reaction times are in the range of 2 to 10 hours and more, for instance 8 hours (the actual reaction time can be monitored by HPLC, TLC or any other appropriate means).
  • the reaction mixture may be filtered, for instance on holes between 0.5 and 5 ⁇ m, preferentially between 0.5 and 1 ⁇ m.
  • the volume of added ethanol is a function of the reaction mixture volume V obtained after step (c) and is preferentially between 0.8 and 1.2 times V, more preferentially between 0.9 and 1.1 times V.
  • the resulting mixture after ethanol addition is heated at a temperature high enough to obtain a homogeneous solution, for instance between 60 and 70° C.
  • the cooling of this resulting solution is usually carried out slowly, preferentially by letting the solution stand for several hours at room temperature and subsequently cooling it and maintaining it for at least 30 min between 0 and 40° C., more preferentially between 0 and 10° C.
  • the first washing is preferentially carried out with a mixture of ethanol/water of typical ratio of at least two volumes of ethanol for 1 volume of water, for instance three volumes of ethanol for 1 volume of water.
  • step (d) the resulting product can be dried in a ventilated oven.
  • the absence of residual ethanol/water can be monitored by NMR. Alternately, this product may be dried by any other suitable methods.
  • a soda solution by mixing 2 L of demineralized water and 0.65 Kg of soda (1.03 equivalents). The obtained solution is made homogeneous at around 5° C. 0.388 Kg of thioacetic acid (1.08 eq) are then added to this solution while maintaining the temperature to around 5° C. 0.1 L of demineralized water is used to rinse the addition funnel containing thioacetic acid and is also added to the reaction mixture. Reactor R is then heated at around 20° C. and stirred at this temperature for 30 min.
  • reactor R′ In a second reactor R′ is placed 1 Kg of sodium bromoethanesulfonate (1.16 eq). To this reactor is added the content of reactor R. Reactor R is rinsed with 0.1 L of demineralized water and the resulting rinsing water is added to reactor R′. Reactor R′ is heated to around 80° C. and stirred at this temperature for around 1 h30. The end of the reaction is monitored by HPLC. The solution is then cooled at around 50° C.
  • a solution of acetic acid is prepared by mixing 0.3 L of demineralized water and 0.3 L of acetic acid. This solution is added to reactor R′.
  • pH is controlled to be in the range of 7.0-7.2 oxygen is bubbled into the reaction mixture while the temperature of the obtained mixture is maintained at around 55° C.
  • pH is checked again and the end of the reaction is monitored by HPLC (if conversion is not complete, oxygen bubbling is continued at a temperature of around 55° C. as long as needed).
  • the reaction mixture is then filtrated on a filter of 1 ⁇ m diameter holes.
  • Ethanol is then added to the filtrated mixture in equal volume and the resulting mixture is thoroughly stirred. Precipitates are eventually forming, which are dissolved by heating at around 65° C. The mixture is then progressively cooled to around 20° C. and may be left standing overnight at this temperature. The resulting mixture is then cooled down to around 5° C. and maintained at this temperature for 1 h. The suspension is then filtrated.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention concerns a novel method for industrial preparation of disodium 2,2′-dithiobis(alkylsulphonates), and in particular disodium 2,2′-dithiobis(ethanesulphate) (dimesna). Said novel method is summarized by the reaction diagram (A). In diagram (A), Hal represents a halogen atom, and preferably a bromine atom; M represents a sodium or potassium atom; and n represents an integer ranging between 0 and 2.

Description

This application is a 371 of PCT/FR01/02312 filed Jul. 17, 2001.
The present invention describes a novel process of industrial preparation of disodium 2,2′-dithiobis(alkylsulfonates), and in particular the preparation of disodium 2,2′-dithiobis(ethanesulfonate) (dimesna).
Dimesna (as well as its monomer, mesna) is a therapeutic agent useful in particular as a chemoprotectant for certain types of cancers by reducing the toxic effect of Platinum complexes commonly used in chemotherapy (like cisplatin). Of relevance is Patent PCT Application WO 98/14426.
A certain number of patent applications are relevant to the processes of preparation of dimesna or mesna. Among them, one can note the PCT application WO 98/14426. The processes related to the preparation of dimesna or homologous products can be summarized in the following scheme. Hal represents a halogen atom and R2 represents a radical SO3M or PO3M2, while M represents sodium, potassium or hydrogen. In the generic formula (IIb) R2 represents exclusively the radical PO3M2:
Figure US06936733-20050830-C00001
In this process, intermediate (III) is not isolated. It is directly transformed by heating in the presence of oxygen to disulfide (Ia).
Another way of preparing symmetric disulfides such as dimesna is described in Phosphorus, Sulfur and Silicon 1994, 95-96, 351-352. This method can be summarized by the following synthetic scheme in which (BTS)2 represents the disulfide of 2-mercaptobenzotriazole:
Figure US06936733-20050830-C00002
A common problem in the synthesis of mesna or dimesna resides in the presence of many impurities in the desired product. These impurities are usually salts like sodium bromide or acetates generated by the current synthetic processes. The necessary removal of such impurities represents an important waste of time and money.
The present invention describes a novel process which allows the synthesis of disodium 2,2′-dithiobis(alkylsulfonates), and in particular the synthesis of mesna, without the common impurities resulting from the previous processes.
This novel process of industrial synthesis of disodium 2,2′-dithiobis(alkylsulfonates) is summarized in the following scheme:
Figure US06936733-20050830-C00003
In the previous scheme, Hal represents a halogen atom, in particular a bromine atom, M represents sodium or potassium atom while n represents an integer from 0 to 2. Steps (a) and (c) are preferentially carried out by heating. M represents preferentially sodium.
This invention is therefore about the industrial preparation process of a disulfide of general formula (I)
Figure US06936733-20050830-C00004
in which n represents an integer from 0 to 2,
with the following steps:
    • (a) treatment of a compound of general formula (II)
      Figure US06936733-20050830-C00005
      in which Hal represents a halogen atom, with a thiolacetate of general formula CH3COSM in which M represents sodium or potassium;
    • (b) reaction of the resulting thiolacetate from step (a) with a base followed by acid neutralization; and
    • (c) reaction of the resulting intermediate sodium mercaptoalkylsulfonate of general formula (III)
      Figure US06936733-20050830-C00006
      with oxygen to yield the disulfide of general formula (I);
      Figure US06936733-20050830-C00007
    • (d) ethanol addition to the resulting reaction mixture from (c), heating to obtain a clear solution, cooling and washing (at least once) of the resulting solid with ethanol.
In this process, sodium thiolacetate CH3COSNa from step (a) can be obtained by reacting thiolacetic acid with a base containing the metallic counterion M, for instance NaOH or KOH when M represents sodium or potassium. Preferentially, M represents sodium, while step (a) is carried out by heating at a temperature superior to ambient temperature, for instance at a temperature between 25 and 100 degree Celsius, particularly between 75 and 85 degree Celsius.
The base necessary to hydrolyze the thiolacetate intermediate in step (b) is preferentially NaOH or KOH. Due to the exothermic character of the reaction, the reaction mixture resulting from step (a) is preferentially cooled to a temperature closer or inferior to ambient temperature (for instance if the preferred temperature for step (a) is between 75 and 85° C., step (b) is preferentially carried out with an initial temperature between 45 and 55° C., or even at a temperature between 0 and 45° C.). After this step, the pH of the reaction mixture should be between 6 and 8, preferentially between 6.5 and 7.5 and more preferentially between 7 and 7.2. The acid used in this neutralization is preferentially acetic acid, although any other suitable acid can be employed.
In step (c), the reaction mixture is preferentially heated at a temperature superior to ambient temperature, for instance at a temperature between 30 and 90° C., preferentially between 50 and 60° C. Oxygen is bubbled in the reaction mixture at a pressure between 0 and 5 bars, preferentially at atmospheric pressure. Alternately, hydrogen peroxide in approximate stoichiometric amounts can be used in place of gaseous oxygen. Reaction times are in the range of 2 to 10 hours and more, for instance 8 hours (the actual reaction time can be monitored by HPLC, TLC or any other appropriate means). After step (c), the reaction mixture may be filtered, for instance on holes between 0.5 and 5 μm, preferentially between 0.5 and 1 μm.
In step (d), the volume of added ethanol is a function of the reaction mixture volume V obtained after step (c) and is preferentially between 0.8 and 1.2 times V, more preferentially between 0.9 and 1.1 times V. The resulting mixture after ethanol addition is heated at a temperature high enough to obtain a homogeneous solution, for instance between 60 and 70° C. The cooling of this resulting solution is usually carried out slowly, preferentially by letting the solution stand for several hours at room temperature and subsequently cooling it and maintaining it for at least 30 min between 0 and 40° C., more preferentially between 0 and 10° C. The first washing is preferentially carried out with a mixture of ethanol/water of typical ratio of at least two volumes of ethanol for 1 volume of water, for instance three volumes of ethanol for 1 volume of water.
After step (d) the resulting product can be dried in a ventilated oven. The absence of residual ethanol/water can be monitored by NMR. Alternately, this product may be dried by any other suitable methods.
This process applies to the preparation of compound (I) where n is preferentially 0, (I) being therefore dimesna.
Unless explicitly defined, all the technical and scientific terms used in this invention have their signification similar to the one commonly understood by an ordinary specialist of the field. All the cited publications, patent applications and patents are mentioned for the sole purpose of references.
The following example illustrates the described procedures and shall not be considered as a limitation of the present invention.
EXAMPLE
Preparation of disodium 2,2′-dithiobis(ethanesulfonate)(dimesna)
In the following procedure the term “around” applied to a temperature corresponds to an interval of ±5° C. around the indicated temperature.
In a first reactor R is prepared a soda solution by mixing 2 L of demineralized water and 0.65 Kg of soda (1.03 equivalents). The obtained solution is made homogeneous at around 5° C. 0.388 Kg of thioacetic acid (1.08 eq) are then added to this solution while maintaining the temperature to around 5° C. 0.1 L of demineralized water is used to rinse the addition funnel containing thioacetic acid and is also added to the reaction mixture. Reactor R is then heated at around 20° C. and stirred at this temperature for 30 min.
In a second reactor R′ is placed 1 Kg of sodium bromoethanesulfonate (1.16 eq). To this reactor is added the content of reactor R. Reactor R is rinsed with 0.1 L of demineralized water and the resulting rinsing water is added to reactor R′. Reactor R′ is heated to around 80° C. and stirred at this temperature for around 1 h30. The end of the reaction is monitored by HPLC. The solution is then cooled at around 50° C.
In another reactor is prepared a soda solution by mixing 2 L of demineralized water and 1.36 Kg of soda. The obtained solution is made homogeneous at around 20° C. This resulting solution is added in reactor R′ yielding an exothermic reaction. The resulting reaction mixture is stirred for around 30 min. . The end of the reaction is monitored by HPLC. The solution is then brought to around 55° C.
In another different reactor, a solution of acetic acid is prepared by mixing 0.3 L of demineralized water and 0.3 L of acetic acid. This solution is added to reactor R′. Once pH is controlled to be in the range of 7.0-7.2 oxygen is bubbled into the reaction mixture while the temperature of the obtained mixture is maintained at around 55° C. After 8 h of bubbling, pH is checked again and the end of the reaction is monitored by HPLC (if conversion is not complete, oxygen bubbling is continued at a temperature of around 55° C. as long as needed). The reaction mixture is then filtrated on a filter of 1 μm diameter holes.
Ethanol is then added to the filtrated mixture in equal volume and the resulting mixture is thoroughly stirred. Precipitates are eventually forming, which are dissolved by heating at around 65° C. The mixture is then progressively cooled to around 20° C. and may be left standing overnight at this temperature. The resulting mixture is then cooled down to around 5° C. and maintained at this temperature for 1 h. The suspension is then filtrated.
In another reactor is prepared an ethanolic solution by mixing 0.1875 L of demineralized water and 0.5625 L of ethanol. This solution made homogeneous at 20° C. is used to wash the resulting “cake” obtained from the previous suspension. The “cake” is washed another time with 0.75 L of ethanol and the solid is dried in a ventilated oven at 60° C. until NMR displays no more ethanol. 0.70 Kg of dimesna are then obtained.

Claims (10)

1. A process for the industrial preparation of a disulfide of formula (I)
Figure US06936733-20050830-C00008
in which n represents an integer between 0 and 2, said process comprising the following steps:
(a) providing a solution containing a compound of formula (II)
Figure US06936733-20050830-C00009
in which Hal represents a halogen atom, and reacting the formula II compound with a thioacetate of the formula CH3C(O)SM in which M represents sodium or potassium to form a thioacetate alkane sulfonate intermediate;
(b) reacting the thioacetate intermediate from step (a) with a base to remove the acetate moiety and form a sodium mercaptoalkanesulfonate intermediate of formula III

HS—CH2CH2—(CH2)n—SO3Na (III);
(c) adjusting the pH of the solution by adding an acid;
(d) reacting the intermediate sodium mercaptoalkanesulfoflate of formula III with oxygen to yield the formula (I) disulfide; and
(e) adding ethanol to the formula I disulfide obtained in step (d), followed by heating to dissolve the precipitates, then cooling and washing the resulting solid with ethanol.
2. Process according to claim 1, in which M represents sodium in step (a).
3. Process according to claim 1 or 2, in which the base in step (b) is sodium hydroxide.
4. Process according to claim 3, in which the volume of ethanol added during step (e) is in between 0.8 and 1.2 times the volume of the reaction mixture obtained at step (d).
5. Process according to claim 4, in which the volume of ethanol added during step (e) is in between 0.9 and 1.1 times the volume of the reaction mixture obtained at step (d).
6. Process according to claim 1, in which the washing of step (e) includes a first step of washing with a mixture of ethanol/water, with a ratio of 2 volumes of ethanol per volume of water.
7. Process according to claim 1, in which the washing of step (e) includes a first step of washing with a mixture of ethanol/water, with a ratio of 3 volumes of ethanol per volume of water.
8. Process according to claim 1, in which step (d) is followed by a filtration of the reaction mixture on a filter of hole sizes comprised between 0.5 and 5 μm, which is carried out just before step (e).
9. Process according to claim 8, in which the filter has hole sizes comprised between 0.5 and 1 μm.
10. Process according to claim 1, in which n=0.
US10/333,422 2000-07-18 2001-07-17 Method for preparing disodium 2,2'-dithiobis(ethanesulphonate) Expired - Lifetime US6936733B2 (en)

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FR0009386A FR2811987A1 (en) 2000-07-18 2000-07-18 PROCESS FOR THE PREPARATION OF DISODIUM 2,2'-DITHIOBIS(ETHANESULFONATE)
FR00/09386 2000-07-18
PCT/FR2001/002312 WO2002006216A1 (en) 2000-07-18 2001-07-17 Method for preparing disodium 2.2'-dithiobis(ethanesulphonate)

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US6504049B1 (en) 2002-04-30 2003-01-07 Bionumerik Pharmaceuticals, Inc. Process for synthesizing pharmaceutically active disulfide salts
JP4936898B2 (en) * 2003-12-17 2012-05-23 バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド Synthesis method of disulfides
JP5109081B2 (en) * 2006-04-26 2012-12-26 東洋紡株式会社 Method for producing thiocarboalkylalkanesulfonate, mercaptoalkanesulfonate and dithiobis (alkanesulfonate) salt using alkenesulfonate
ATE501117T1 (en) * 2007-08-03 2011-03-15 Ucb Pharma Sa SULFANYL DERIVATIVES AND THEIR USE AS SYNTHETIC INTERMEDIATE PRODUCTS
CA2706571C (en) 2007-12-19 2012-11-27 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
CN102584657B (en) * 2011-12-27 2014-06-11 杭州海虹精细化工有限公司 Preparation method of persulfide/sulfide zinc acetate
KR102295590B1 (en) * 2013-04-19 2021-08-30 가부시키가이샤 도우사 고가쿠 겐큐쇼 Method for producing activated sugar-chain derivative, and activated sugar-chain derivative
CN114287785B (en) * 2021-11-24 2023-08-25 吉祥三宝高科纺织有限公司 Pregnant woman pillow
CN114853645B (en) * 2022-04-22 2025-02-11 苏州亚科科技股份有限公司 A preparation process of sodium polydisulfide dipropane sulfonate
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